Copolymer compositions adapted for use in controlled release delivery systems such as biodegradable and bioerodible implants are known. Polyesters such as poly(DL-lactide-glycolide) (“PLG”) copolymers can be used, as the ester linkages are readily degraded in body tissues by endogenous esterases as well as by uncatalyzed hydrolytic cleavage yielding non-toxic, water-soluble hydrolysis products, and controlled release systems incorporating PLG copolymers have been widely described. See, for example, U.S. Pat. Nos. 7,019,106; 6,565,874; 6,528,080; RE37,950; 6,461,631; 6,395,293; 6,355,657; 6,261,583; 6,143,314; 5,990,194; 5,945,115; 5,792,469; 5,780,044; 5,759,563; 5,744,153; 5,739,176; 5,736,152; 5,733,950; 5,702,716; 5,681,873; 5,599,552; 5,487,897; 5,340,849; 5,324,519; 5,278,202; and 5,278,201. Such controlled release systems are in general advantageous because they provide for the controlled and sustained release of medications, often directly at or near the desired site of action, over the period of days, weeks or even months. Polyesters including poly-lactide, poly-glycolide, and copolymers thereof (“PLG copolymers”) can be prepared from glycolide (1,4-dioxan-2,5-dione, glycolic acid cyclic dimer lactone) and lactide (3,6-dimethyl-1,4-dioxan-2,5-dione, lactic acid cyclic dimer lactone), or from glycolate (2-hydroxyacetate) and lactate (2-hydroxypropionate). These copolymer materials are particularly favored for this application due to their facile breakdown in vivo by body fluids or enzymes in the body to non-toxic materials, and their favorable properties in temporally controlling the release of medicaments and biologically active agents (“bioactive agents”) that may be contained within a mass of the controlled release formulation incorporating the polymer that has been implanted within a patient's body tissues. Typically, controlled release systems are adapted to provide for as constant a rate of release as possible of the bioactive agent over the time period that the implant persists within the body.
Flowable delivery systems, such as the Atrigel® systems, are disclosed in U.S. Pat. Nos. 6,565,874, 6,528,080, 6,461,631, 6,395,293, and references found therein. Flowable delivery systems like the Atrigel® system include a biodegradable polymer such as a PLG copolymer, a bioactive agent, and an organic solvent that has at least a very slight solubility in body fluids. When the substantially liquid (“flowable”) solution of the delivery system is injected into a patient's tissues, typically as a single bolus, the organic solvent diffuses into surrounding body fluids, causing precipitation or gelation of the water-insoluble polymer containing the bioactive agent. It is believed that initially a skin forms on the deposited liquid mass, bringing about formation of the semi-solid deposit known as a depot that contains the remaining solution of the polymer and the bioactive agent in the solvent. As the depot resides in the tissues, the solvent continues to diffuse out and body fluids to diffuse in, bringing about ongoing precipitation of the polymer with the bioactive agent, until a gelled or solid mass remains. Channels or pores may form in the depot as part of this process. Due to the biodegradable nature of the polymer in the presence of body fluids and of enzymes within the body, the polymer slowly degrades into soluble non-toxic hydrolysis products, releasing the contained bioactive agent over a period of time. This process continues until the depot is substantially completely dissolved and all the bioactive agent is released. It is understood that such depots can be adapted to persist for various lengths of time within the body, such as about 30 days, about 60 days, or about 3 months, 4 months, or 6 months.
In this manner, a relatively constant level of the bioactive agent can be maintained within the patient's body for the period of time over which the formulation is adapted to release the agent. It is generally undesirable to have fluctuations in the rate of release, and thus in the levels within the patient's body, of the bioactive agent following as well as during the initial period following administration of the formulation to the patient. For example, it is undesirable to have an increasing rate of release or a decreasing rate of release, or to have the rate of release peak at some time point and then decline, during the entire time period for which the formulation is adapted to release the bioactive agent. The most desirable rate of release is typically a constant, or zero-order, rate of release, wherein the amount of the bioactive agent released per time interval is constant, up until the point of complete dissolution of the controlled release implant in the patient's body.
At least two problems involving a less than optimal rate of release have been found using art PLG copolymers in controlled release systems: an initial burst effect, and a degree of variability in the subsequent rate of release over the lifetime of the depot in the body. It has been found that the release of many bioactive agents such as peptides, proteins, and small molecule drugs from controlled release systems can occur at a higher than optimal rate during the first 24 hours after implantation under certain conditions. This is known in the art as the “burst effect” or the “initial burst effect,” and is generally undesirable, as overdosing of the patient can result. A number of approaches to the solution of the burst effect problem have been described, as are discussed below. The second effect involves a variable, non-linear rate of release of the bioactive agent as the implanted formulation undergoes its period of degradation in the body that deviates from linearity or zero-order kinetics. This effect can occur when using purified copolymer formulations adapted to reduce or minimize the initial burst effect as well as when using unpurified copolymers. After a depot has been formed within a patient's body by introduction of a flowable delivery system, it has been observed on occasion that the rate of release of the bioactive agent tends to vary. Thus, while the depot is present within the body an increase or a decrease or a variation in rate of delivery of the bioactive agent occurs, which is generally undesirable.